Project Summary/Abstract The United States has the largest (43 million in 2012) aging population (>65 years of age) among developed countries and will reach 73 million by 2030. Heart failure (HF) is becoming an epidemic among increasing population of aging Americans. Medical costs of HF are projected to be $53 billion. HF patients are classified by its ejection fraction (EF) (reduced: preserved: intermediate = 40% : 50% : 10%). While various treatment options including devices are available for HF with reduced EF (HFrEF), no efficacious therapies have been identified for HF with preserved EF (HFpEF). Lack of good models including animal model to understand the mechanism have been impairing the discovery of effective treatments. Hutchinson?Gilford progeria syndrome (HGPS, progeria) is an ultra-rear disease that prematurely exhibits multiple features of aging. A single-base substitution, G608G(GGC > GGT), in LMNA was discovered to produce an abnormal lamin A protein, progerin, and cause HGPS. The most recent study of 27 HGPS patients (2-17 years) showed their development of asymptomatic left ventricular diastolic dysfunction, the precursor to HFpEF. Therefore, we hypothesize that the HGPS model develops HFpEF phenotype in vitro quicker than control, which provides an unprecedented opportunity to understand the mechanisms of HFpEF pathogenesis and a tool to discover new treatments. We will develop 3D micro hearts, called ?NuHeart??, growing in 96- and 384- well plates using gene-edited iPSCs of HGPS based on healthy donor iPSCs (free from any known HF mutations) The proposed analyses will evaluate the model's applicability in mimicking naturally aging heart developing HFpEF and their use for drug discovery.